Method for treating cancers having high glucose requirements employing an sglt2 inhibitor and compositions thereof

ABSTRACT

Methods are provided for treating cancers that have high glucose requirements and that express SGLT2 at levels higher than normal cells, such as metastatic cancers, for example, metastatic lung cancers, employing an SGLT2 inhibitor alone or in combination with a cytotoxic agent and to a composition containing a combination of an SGLT2 inhibitor and a cytotoxic agent.

This application claims priority to U.S. Provisional Ser. No.61/037,509, filed on Mar. 18, 2008, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to a method for treating cancers that have highglucose requirements and that express SGLT2 at levels higher than normalcells, comprising administering an SGLT2 inhibitor alone or incombination with a cytotoxic agent, and to compositions thereof.

BACKGROUND OF THE INVENTION

It is known that cancer cells need increased glucose uptake andutilization as compared to normal cells. Uptake of glucose in cells,including cancer cells, is facilitated by glucose transporters includingNa⁺/glucose cotransporter-2 (SGLT2), that utilize the electrochemicalsodium gradient to transport glucose against the cells internalconcentration gradient.

Researchers have reported that SGLT2 expression was significantly higherin the metastatic lesions in the liver and lymph node than in theprimary lung cancers. SGLT1 expression in the primary lung cancers andtheir metastatic lesions did not significantly differ. These resultsindicate that SGLT2 plays a role in glucose uptake in the metastaticlesions of lung cancer.

The inhibition of SGLT2 as a means to reduce glucose uptake in cancercells represents a viable therapeutic method for treating cancers.Therefore, compounds or agents that inhibit SGLT2 are attractive targetsfor treating cancers that have increased expression of SGLT2, such asmetastatic lesions associated with lung cancer.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method for treating cancers thatexpress SGLT2 at a level higher than normal cells in a mammal comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of an SGLT2 inhibitor.

In another aspect, the invention provides a method for treating cancersthat express SGLT2 at higher levels than normal cells in a mammalcomprising administering to the mammal in need of such treatment atherapeutically effective amount of a pharmaceutical compositioncomprising an SGLT2 inhibitor and at least one pharmaceuticallyacceptable carrier, excipient, or diluent.

In another aspect, the invention provides a method for treating cancersthat express SGLT2 at higher levels than normal cells in a mammalcomprising administering to the mammal in need of such treatment atherapeutically effective amount of an SGLT2 inhibitor and a cytotoxicagent where the cytotoxic agent is administered prior to, after, orconcurrently with the SGLT2 inhibitor.

In another aspect, the invention provides a method for treating cancersthat express SGLT2 at higher levels than normal cells in a mammalcomprising administering to the mammal in need of such treatment atherapeutically effective amount of a pharmaceutical compositioncomprising an SGLT2 inhibitor, a cytotoxic agent and at least onepharmaceutically acceptable carrier, excipient, or diluent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts bar graphs showing an indirect comparison of the amountof glucose excretion in urine/day caused by each of the SGLT2 inhibitorsGSK 869,682 and Compound Ia; and

FIG. 2 depicts a series of graphs showing urine glucose excretion indiabetic subjects treated with Compound Ia and placebo.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides a method for treating lung cancermetastatic lesions in a mammal comprising administering to the mammal inneed of such treatment a therapeutically effective amount of an SGLT2inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a mammal comprising administering to themammal in need of such treatment a therapeutically effective amount of apharmaceutical composition comprising an SGLT2 inhibitor and at leastone pharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a mammal comprising administering to themammal in need of such treatment a therapeutically effective amount ofan SGLT2 inhibitor and a cytotoxic agent where the cytotoxic agent isadministered prior to, after, or concurrently with the SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a mammal comprising administering to themammal in need of such treatment a therapeutically effective amount of apharmaceutical composition comprising an SGLT2 inhibitor, a cytotoxicagent and at least one pharmaceutically acceptable carrier, excipient,or diluent.

In one aspect, the invention provides a method for treating lung cancermetastatic lesions in a human comprising administering to the human inneed of such treatment a therapeutically effective amount of an SGLT2inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a human comprising administering to thehuman in need of such treatment a therapeutically effective amount of apharmaceutical composition comprising an SGLT2 inhibitor and at leastone pharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a human comprising administering to thehuman in need of such treatment a therapeutically effective amount of anSGLT2 inhibitor and a cytotoxic agent where the cytotoxic agent isadministered prior to, after, or concurrently with the SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in a human comprising administering to thehuman in need of such treatment a therapeutically effective amount of apharmaceutical composition comprising an SGLT2 inhibitor, a cytotoxicagent and at least one pharmaceutically acceptable carrier, excipient,or diluent.

In one aspect, the invention provides a method for treating lung cancermetastatic lesions in the liver of a human comprising administering tothe human in need of such treatment a therapeutically effective amountof an SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the liver of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor and at least one pharmaceutically acceptable carrier,excipient, or diluent.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the liver of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of an SGLT2 inhibitor and a cytotoxic agent where thecytotoxic agent is administered prior to, after, or concurrently withthe SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the liver of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor, a cytotoxic agent and at least one pharmaceuticallyacceptable carrier, excipient, or diluent.

In one aspect, the invention provides a method for treating lung cancermetastatic lesions in the lymph nodes of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of an SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the lymph nodes of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor and at least one pharmaceutically acceptable carrier,excipient, or diluent.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the lymph nodes of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of an SGLT2 inhibitor and a cytotoxic agent where thecytotoxic agent is administered prior to, after, or concurrently withthe SGLT2 inhibitor.

In another aspect, the invention provides a method for treating lungcancer metastatic lesions in the lymph nodes of a human comprisingadministering to the human in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor, a cytotoxic agent and at least one pharmaceuticallyacceptable carrier, excipient, or diluent.

In another aspect, the invention provides a use of an SGKT2 inhibitor inthe manufacture of a medicament for treating lung cancer metastaticlesions.

In another aspect, the invention provides a combination of a SGLT2inhibitor and a cytotoxic agent as a medicament for treating lung cancermetastatic lesions, where the cytotoxic agent is administered prior to,after, or concurrently with the SGLT2 inhibitor.

In another aspect, the invention provides a use of an SGKT2 inhibitor inthe manufacture of a medicament for treating lung cancer metastaticlesions in the liver.

In another aspect, the invention provides a combination of a SGLT2inhibitor and a cytotoxic agent as a medicament for treating lung cancermetastatic lesions in the liver, where the cytotoxic agent isadministered prior to, after, or concurrently with the SGLT2 inhibitor.

In another aspect, the invention provides a use of an SGKT2 inhibitor inthe manufacture of a medicament for treating lung cancer metastaticlesions in the lymph nodes.

In another aspect, the invention provides a combination of a SGLT2inhibitor and a cytotoxic agent as a medicament for treating lung cancermetastatic lesions in the lymph nodes, where the cytotoxic agent isadministered prior to, after, or concurrently with the SGLT2 inhibitor.

The SGLT2 inhibitor is employed in a weight ratio to the optionalcytotoxic agent in an amount within the range from about 200:1 to about0.1:1, preferably from about 100:1 to about 0.2:1.

The dosage for the cytotoxic agent (used in combination with the SGLT2inhibitor) will be the recommended doses for such cytotoxic agents asdisclosed in the latest PHYSICIANS' DESK REFERENCE (PDR) or REMINGTON'SPHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, Pa.).

The SGLT2 inhibitor employed in the above-defined methods of theinvention will not cause hypoglycemia in non-diabetic humans that is ahuman who does not suffer from hyperglycemia, and will not causehypoglycemia in diabetic humans as well.

In preferred embodiments of all aspects of the invention, the SGLT2inhibitor will be administered in amounts below the therapeutic amount(sub-therapeutic amount) as prescribed in generally accepted medicalpractice for treating diabetes.

The SGLT2 inhibitor employed in the invention is selective for SGLT2relative to SGLT-1. Higher SGLT2: SGLT-1 selectivity ratios result ingreater effectiveness at eradicating cancer cells.

In carrying out the methods of the invention for treating cancers whichexpress SGLT2 at levels higher than normal cells, the SGLT2 inhibitormay be administered to a patient in need of treatment in a cancertreating amount which can be as high as that which may be used to treatcancers but less than an amount which could cause hypoglycemia. Thedaily dose may be lowered as successful treatment of cancer cells isachieved. For example, depending upon the patient, and the specificSGLT2 inhibitor employed, the SGLT2 inhibitor may be orally administeredin a cancer treating amount from about 1 to about 1000 mg per day,preferably from about 2 to about 400 mg/day, preferably 2.5 to about 75mg/day, and more preferably 20 to about 50 mg/day, which can beadministered in a single dose or in the form of individual doses from 1to 4 times per day.

The SGLT2 inhibitor may be administered by injection to a patient in acancer treating amount from about 1 to about 100 mg/day, preferably fromabout 1 to about 30 mg/day.

The SGLT2 inhibitor suitable for use in accordance with the inventionwill be a C-arylglucoside or an O-arylglucoside.

Examples of C-arylglucoside (also referred to as C-glucosides) SGLT2inhibitors which may be employed in the method of the invention,include, but are not limited to the following:

1) Compound I or dapagliflozin

preferred for use in the invention and its corresponding tetraacetateshown below as compound II

as disclosed in U.S. Pat. No. 6,515,117, (PCT/US03/15591) the disclosureof which is incorporated herein by reference in its entirety for anypurpose.

2) Compounds of formula III:

wherein

R¹, R² and R^(2a) are independently hydrogen, OH, OR⁵, alkyl, CF₃,OCHF₂, OCF₃, SR^(5i) or halogen, or two of R¹, R² and R^(2a) togetherwith the carbons to which they are attached can form an annelated five-,six- or seven-membered carbocycle or heterocycle which may contain 1 to4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂;

R³ and R⁴ are independently hydrogen, OH, OR^(5a), OAryl, OCH₂Aryl,alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5b), —CO₂H,—COR^(6b), —CH(OH)R^(6c), —CH(OR^(5h))R^(6d), —CONR⁶R^(6a), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl, or a five, six or seven membered heterocycle which may contain1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³and R⁴ together with the carbons to which they are attached form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂;

R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h) andR^(5i) are independently alkyl;

R⁶, R^(6a), R^(6b), R^(6c) and R^(6d) are independently hydrogen, alkyl,aryl, alkylaryl or cycloalkyl, or R⁶ and R^(6a) together with thenitrogen to which they are attached form an annelated five, six or sevenmembered heterocycle which may contain 1 to 4 heteroatoms in the ringwhich are N, O, S, SO, and/or SO₂;

A is O, S, NH, or (CH₂)_(n) where n is 0-3,

and pharmaceutically-acceptable salts thereof, all stereoisomersthereof, and all prodrug esters thereof.

The compounds of formula III as defined above also include compoundswherein where A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is 0, and atleast one of R¹, R², and R^(2a) is OH or OR⁵, then at least one of R¹,R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴is CF₃, —OCHF₂, CH(OR^(5h))R^(6d), CH(OH)R^(6c), COR^(6b), —CN,—CO₂R^(5b), —NHCOR^(5c), —NHSO₂R^(5d), —NHSO₂Aryl, aryl, —SR^(5e),—SOR^(5f), —SO₂R^(5g) or —SO₂Aryl.

Preferred compounds of formula III as defined above compounds whereinwhere A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is O, and at leastone of R¹, R², R^(2a), R³ and R⁴ is OH or OR⁵, then at least one of R′,R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴is CF₃, —OCHF₂, —CN, —CO₂R^(5b), CH(OR^(5h))R^(6d), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl or halogen.

Preferred for use herein is compound IIIA, shown below, disclosed inU.S. Pat. No. 6,414,126 (PCT/US00/27187).

3) C-aryl glucosides that are crystalline complexes of amino acids, suchas L-proline and D-phenylalanine complexes, as disclosed in U.S. Pat.No. 6,774,112 (PCT/US02/11066) (the disclosure of which is incorporatedherein by reference in its entirety) as follows:

wherein

R¹, R² and R^(2a) are independently hydrogen, OH, OR⁵, alkyl, —OCHF₂,—OCF₃, —SR^(5a) or halogen;

R³ and R⁴ are independently hydrogen, OH, OR^(5b), alkyl, cycloalkyl,CF₃, —OCHF₂, —OCF₃, halogen, —CONR⁶R^(6a), —CO₂R^(5c), —CO₂H, —COR^(6b),—CH(OH)R^(6c), —CH(OR^(5d))R^(6d), —CN, —NHCOR^(5e), —NHSO₂R^(5f),—NHSO₂Aryl, —SR^(5g), —SOR^(5h), —SO₂R^(5f), or a five-, six- orseven-membered heterocycle which may contain 1 to 4 heteroatoms in thering which are N, O, S, SO, and/or SO₂, or R³ and R⁴ together with thecarbons to which they are attached form an annelated five, six or sevenmembered carbocycle or heterocycle which may contain 1 to 4 heteroatomsin the ring which are N, O, S, SO, SO₂;

R⁵, R^(5a), R^(6b), R^(6c), R^(6d), R^(6e), R^(5f), R^(5g), R^(5h) andR^(5i) are independently alkyl; and

R⁶, R^(6a), R^(6b), R^(6a) and R^(6d) are independently hydrogen, alkyl,aryl, alkylaryl or cycloalkyl, or R⁶ and R^(6a) together with thenitrogen to which they are attached form an annelated five-, six- orseven-membered heterocycle which may contain 1 to 4 heteroatoms in thering which are N, O, S, SO, and/or SO₂.

Preferred compounds of formula IV include the L-proline andD-phenylalanine complexes wherein R¹ is p-Cl, and R³ is p-C₂H₅ orp-OC₂H₅;

4) Glucopyranosyl-substituted benzene derivatives or salts thereof asdisclosed in US 2005/0209166 (the disclosure of which is incorporated byreference in its entirety) as follows:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(7a), R^(7b) and R^(7a) are as definedin US 2005/0209166.

5) D-pyranosyl-substituted phenyls as disclosed in US 2006/0074031 (thedisclosure of which is incorporated herein by reference in its entirety)as follows:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R^(7c), X and Z are asdefined in US 2006/0074031.

6) D-xylopyranosyl-substituted cycles or salts thereof as disclosed inUS 2006/0035841 (the disclosure of which is incorporated herein byreference in its entirety) as follows:

wherein

denotes a single or double bond, and

Cy, R¹, R², R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R^(7a), X and Z are asdefined in US 2006/0035841.

7) D-xylopyranosyl-substituted phenyls or salts thereof as disclosed inUS 2006/0009400 (the disclosure of which is incorporated herein byreference in its entirety) as follows

wherein R¹, R², R³, R⁴, R⁵, R^(7a), R^(7b), R^(7c), X and Z are asdisclosed in US 2006/0009400.

8) D-glucopyranosyl-phenyl-substituted cycles and salts thereof asdisclosed in US 2006/0025349 (the disclosure of which is incorporatedherein by reference in its entirety) as follows:

wherein

denotes a single or double bond, and

Cy, R¹, R², R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R^(7c), R^(7d) and Z are asdefined in US 2006/0025349.

9) C-glycoside derivatives and salts thereof as disclosed in US2006/0122126 (the disclosure of which is incorporated herein byreference in its entirety) as follows:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, X, A and B are asdefined in US 2006/0122126.

10) D-xylopyranosyl-substituted phenyls as disclosed in US 2006/0019948(the disclosure of which is incorporated herein by reference in itsentirety) as follows:

wherein R¹, R², R³, R⁴, R⁵, R^(7a), R^(7b), R^(7c), X and Z are asdefined in US 2006/0019948.

Examples of O-glucoside SGLT2 inhibitors which may be employed in themethod of the invention include, but are not limited to the following:

1) 5-Thio-β-D-glucopyranosides or salts or hydrates thereof as disclosedin US 2006/0194809 (the disclosure of which is incorporated by referencein its entirety) as follows:

wherein R^(1A), R^(2A), R^(3A), R^(4A), R⁵, R⁶, R⁷, R⁸, R⁹, Q^(x), X^(A)and B are as defined in US 2006/0194809.

2) Glucopyranyloxybenzene derivatives as disclosed in WO 03/01180 (thedisclosure of which is incorporated by reference in its entirety) asfollows:

wherein

R¹ represents hydrogen, hydroxyl, optionally substituted amino, cyano,carbamoyl, optionally substituted lower alkyl, optionally substitutedlower alkoxy, or optionally substituted cyclic amino;

R² represents hydrogen or lower alkyl; and

R³ represents optionally substituted aryl, optionally substitutedcycloalkyl, an optionally substituted aliphatic heterocyclic group, oran optionally substituted aromatic heterocyclic group, apharmacologically acceptable salt of the derivative, or a prodrug ofeither.

3) Pyrazole derivatives or salts thereof as disclosed in U.S. Pat. No.6,908,905 (the disclosure of which is incorporated herein by referencein its entirety) as follows:

wherein X represents β-D-glucopyranosyl group, wherein one or morehydroxyl groups may be acylated; Y represents a lower alkyl group or aperfluoro lower alkyl group; Z represents a cyclic alkyl group which mayhave a substituent(s), a cyclic unsaturated alkyl group which may have asubstituent(s), a lower alkyl group having a cyclic alkyl group whichmay have a substituent(s), or a lower alkyl group having a cyclicunsaturated alkyl group which may have a substituent(s); R¹ to R⁵ may bethe same or different and each represent a hydrogen atom, a lower alkylgroup, a perfluoro lower alkyl group, a lower alkyloxy group, aperfluoro lower alkoxyl group, a lower alkylthio group, a perfluorolower alkylthio group, a lower alkylamino group, a halogen group, alower alkanoyl group, an alkenyl group, a cyclic alkenyl group, analkynyl group, a phenyl group which may have a substituent(s), or alower alkoxycarbonyl group; and n is an integer of 0 to 3 including:

4) Pyrazole compounds or salts thereof as disclosed in U.S. Pat. No.6,815,428 (the disclosure of which is incorporated herein by referencein its entirety) as follows:

wherein X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated or a β-D-glucuronyl group, of which oneor more hydroxyl groups may be acylated and a carboxyl group may beesterified; Y represents a lower alkyl group or a perfluoro lower alkylgroup; Z represents a hydrogen atom, a lower alkyl group, a perfluorolower alkyl group, an aralkyl group or a phenyl group; R¹, R², R⁴ and R⁵may be the same or different and each represents a hydrogen atom, alower alkyl group, a perfluoro group, a lower alkoxy group, a fluorolower alkoxy group, a lower alkylthio group, a perfluoro lower alkylthiogroup, a lower alkyl amino group, a halogen group, a lower alkanoylgroup, a lower alkenyl group or a lower alkynyl group; and n representsan integer from 0 to 3,

wherein at least one of R¹, R², R⁴ and R⁵ represents a lower alkyl grouphaving 1 to 6 carbon atoms, lower alkylthio group having 1 to 6 carbonatoms, halogen atom, lower alkoxy group lower alkenyl group or loweralkynyl group; and

R³ represents a lower alkyl group having a 1 to 6 carbon atoms, a loweralkylthio group having 1 to 6 carbon atoms, a halogen atom, a loweralkoxy group, a lower alkenyl group, or a lower alkynyl group.

5) O-glucosylated benzamides or salts thereof as disclosed in U.S. Pat.No. 6,555,519 (the disclosure of which is incorporated herein byreference in its entirety) as follows:

wherein

n is 0, 1 or 2;

A is

or heteroaryl which may contain 1 to 4 heteroatoms in the ring which maybe selected from N, O, S, SO, and/or SO₂ bearing substituents R³ and R⁴;

R¹ is selected from hydrogen, OR^(S), lower alkyl, aryl, arylalkyl,NHCOR⁵, NR⁶R^(6a), or halogen;

R² is selected from hydrogen, OH, OR^(5a), or lower alkyl;

R³ an R⁴ are the same or different and are independently selected fromhydrogen, OH, OR^(5b), OAryl, OCH₂Aryl, lower alkyl, cycloalkyl, aryl,arylalkyl, CF₃, —SCF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5c), —CO₂H,—CONR^(6b), R^(6c), —NR^(6d)R^(6e), —SO₂NH₂, —NHCOR^(5d),—NHSO₂R^(5e)—NHSO₂Aryl, —SR^(5f), —SOR^(5g), —SO₂R^(5h), —SO₂Aryl,—OCH₂CO₂R^(5i), —OCH₂CO₂H, —OCH₂CONR^(6f)R^(69g), —OCH₂CH₂NR^(6h)R^(6i),or a five-, six- or seven-membered heterocycle which may contain 1 to 4heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³ and R⁴together with the carbons to which they are attached form an annelatedfive-, six- or seven-membered carbocycle or heterocycle which maycontain 1 to 4 heteroatom in the ring which are N, O, S, SO, and/or SO₂;

R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5i), andR^(5i) are independently lower alkyl; and

R⁶, R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), R^(6g), R^(6h), andR^(6i) are the same or different and are independently selected fromhydrogen, alkyl, aryl, arylalkyl or cycloalkyl.

6) O-aryl glucosides or salts thereof as disclosed in U.S. Pat. No.6,683,056 (the disclosure of which is incorporated herein by referencein its entirety) as follows:

wherein

when Y is

or heteroaryl;

R¹, R², R³, and R⁴ are the same or different and are independentlyselected from hydrogen, OH, OR⁷, lower alkyl, or halogen, or two of R¹,R², R³, and R⁴ together with the carbons to which they are attached canform an annelated five-, six- or seven-membered carbocycle orheterocycle which may contain 1 to 4 heteroatoms in the ring which areN, O, S, SO, and/or SO₂;

R⁵ and R⁶ are the same or different and are independently selected fromhydrogen, OH, OR^(7a), —OAryl, —OCH₂Aryl, lower alkyl, cycloalkyl, aryl,arylalkyl, CF₃, arylalkenyl, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(7b),—CO₂H, COR^(8f), CHOHR^(8g), CH(OR^(7h))R^(8h), —CONR⁸R^(8a),—NHCOR^(7c), —NHSO₂R^(7d), —NHSO₂Aryl, —SR^(7e), —SOR^(7f), —SO₂R^(7g),—SO₂Aryl, —OCH₂CO₂R^(7i), —OCH₂CO₂H, —OCH₂CONR^(8b)R^(8c),—OCH₂CH₂NR^(8d)R^(8e), or a five-, six- or seven-membered heterocyclewhich may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO,and/or SO₂, or R⁵ and R⁶ together with the carbons to which they areattached form an annelated five-, six- or seven-membered carbocycle orheterocycle which may contain 1 to 4 heteroatoms in the ring which areN, O, S, SO, and/or SO₂;

R⁷, R^(7a), R^(7b), R^(7e), R^(7d), R^(7e), R^(7f), R^(7g), R^(7h), andR^(7i) are independently lower alkyl;

R⁸, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), and R^(8h)are the same or different and are independently selected from hydrogen,alkyl, aryl, arylalkyl, cycloalkyl, or together with the nitrogen towhich they are attached form an annelated five-, six- or seven-memberedheterocycle which may contain 1 to 4 heteroatoms in the ring which areN, O, S, SO, and/or SO₂; and

A is O(CH₂)_(m), S, NH(CH₂)_(m), or (CH₂)_(n) where n is 0-3 and m is0-2.

Other O-aryl glucosides SGLT2 inhibitors which may be used in theinvention are disclosed in the following references all of which areincorporated herein by reference.

1) EP 598359A1 (also JP 035988) (and any U.S. counterpart applications)(Tanabe Seiyaku) discloses compounds of the following structure

2) EP 0850948A1 (and any U.S. counterpart applications) discloses thefollowing structures of genus

3) JP 09188625A (and any U.S. counterpart applications) expands uponstructure XXI (of EP 0850948A1) to include examples of XXI where R³ is Hand where the five-membered ring is saturated as well as thecounterparts of benzothiophenes (O═S) and indenes (O═CH₂). EP 684254-A1appears to encompass derivatives of structure XXI disclosed in JP09188625A.

4) JP 09124685A (and any U.S. counterpart applications) expands uponstructure XXI for R³=H to include derivatives of mono acylated C6hydroxyl where the acyl group is a substituted benzoic or pyridylcarboxylic acid or a urethane generated from the corresponding phenol.

5) JP 09124684 (and any U.S. counterpart applications) disclosesderivatives of structure XXI

6) EP 773226-A1 (and any U.S. counterpart applications) disclosesderivatives of structure XXI

7) JP 08027006-A (and any U.S. counterpart applications) disclosesderivatives of structure XX where various combinations of the glucosehydroxyl are acylated and appears to be similar to EP 598359A1.

8) EP 684254-A1 (and any U.S. counterpart applications) appears toencompass derivatives of structure XXI disclosed in JP 09188625A.

Other disclosures and publications which disclose SGLT2 inhibitors thatcan be employed according to the methods of the invention are asfollows:

9) K. Tsujihara et al., Chem. Pharm. Bull., 44:1174-1180 (1996);

10) M. Hongu et al., Chem. Pharm. Bull., 46:22-33 (1998);

11) M. Hongu et al., Chem. Pharm. Bull., 46:1545-1555 (1998); and

12) A. Oku et al., Diabetes, 48:1794-1800 (1999).

13) JP 10245391 (Dainippon) discloses 500 structures as hypoglycemicagents for treatment of diabetes. These are O-glucosides of hydroxylatedcoumarins.

In addition to the above SGLT2 inhibitors, other SGLT2 inhibitors thatcan be employed using the methods disclosed herein include thosedisclosed in US 2005/0233982 (Boehringer Ingelheim Corp.), US2005/0119192 (Kissei Pharmaceutical Co.), WO 2006/035796 (KisseiPharmaceutical Co.), JP 2006/117651 (Taisho Pharmaceutical Co.), JP2004/4359630 (Yamanouchi Pharmaceutical Co.), WO 2006/080421 (ChugaiSeiyaku Kabushiki Kaishi), US 2005/0233988 (Tanabe Seiyaku Co.), WO2005/012321 (Tanabe Seiyaku Co.), U.S. Pat. No. 7,015,201 (AjinomotoCo.), WO 2006/058597 (Merck Patent GmbH), WO 2006/011469 (Chugai SeiyakuKabushiki Kaisha), US 2003/0195235 (Johnson & Johnson), and WO2006/037537 (Boehringer Ingelheim).

Preferred SGLT2 inhibitors for use in the methods and compositions ofthe invention include compound I, compound II, and compound MA:

or pharmaceutically acceptable salts thereof, all stereoisomers thereof,or a prodrug ester thereof;

or pharmaceutically-acceptable salts thereof, all stereoisomers thereof,or prodrug esters thereof;

or a pharmaceutically acceptable salts thereof, all stereoisomersthereof, or a prodrug ester thereof.

Also preferred are crystalline forms of compound I above including thecrystalline forms disclosed in US published patent applicationUS/2008/0004335, the disclosures of which are incorporated herein byreference in their entirety for any purpose. A most preferredcrystalline form of compound I is the (S) propylene glycol solvate orhydrate, compound Ia or dapagliflozin-PGS, shown below. It is to beunderstood the (R) propylene glycol solvate or hydrate is also apreferred compound for use in the methods and compositions of theinvention.

The crystalline structure of compound Ia is characterized by one or moreof the following:

a) unit cell parameters substantially equal to the following:

Cell Dimensions:

a=11.2688(8) Å

b=4.8093(3) Å

c=46.723(3) Å

α=90 degrees

β=90 degrees

γ=90 degrees

Space group=P2₁2₁2₁

Molecules/asymmetric unit=1

wherein measurement of said crystalline structure is at room temperatureand which is characterized by fractional atomic coordinatessubstantially as listed in Table 4 of U.S. Provisional Application No.60/817,118;

b) a powder x-ray diffraction pattern comprising 2θ values (CuKαγ=1.5418 Å) selected from the group consisting of 3.8±0.1, 7.6±0.1,8.1±0.1, 8.7±0.1, 15.2±0.1, 15.7.4±0.1, 17.1±0.1, 18.9±0.1 and 20.1±0.1,at room temperature;

c) a solid state ¹³C NMR spectrum having substantially similar peakpositions at 16.2, 17.6, 39.3, 60.9, 63.3, 69.8, 76.9, 78.7, 79.4,113.8, 123.6, 129.3, 130.5, 132.0, 135.7, 139.1 and 158.0 ppm, asdetermined on a 400 MHz spectrometer relative to TMS at zero;

d) a differential scanning calorimetry thermogram having an endotherm inthe range of about 50° C. to 78° C. or as shown in FIG. 7 of U.S.Provisional Application No. 60/817,118;

e) thermal gravimetric analysis curve with about 18.7% weight loss fromabout room temperature up to about 240° C. or as shown in FIG. 5 of U.S.Provisional Application No. 60/817,118; or

f) having a proton NMR having substantially similar peak positions aslisted in Table 1A of U.S. Provisional Application No. 60/817,118.

A process for the preparation of compound Ia is provided inUS/2008/0004335. Generally, compound II (prepared as described inPCT/US03/041373, Examples 17-19) is treated with aqueous base, such asaqueous sodium hydroxide, in an alcohol solvent, such as methanol,preferably under an inert atmosphere, such as nitrogen, at an elevatedtemperature (between about 5° C. and 85 C) to form compound I

The reaction mixture containing compound I is treated with an organicsolvent such as methyl tert-butyl ether or an alkyl acetate such asethyl acetate, methyl acetate, isopropyl acetate, or butyl acetate, and(S)-propylene glycol, optionally adding seeds of compound Ia to themixture, to provide compound Ia.

The SGLT2 inhibitor employed in accordance with the invention can beadministered to various mammalian species, such as dogs, cats, humans,etc., in need of treatment. These agents can be administeredsystemically, such as orally or parenterally.

The SGLT-2 inhibitor can be incorporated in a conventional systemicdosage form, such as a tablet, capsule, elixir or injectableformulation. The above dosage forms will also include the necessaryphysiologically acceptable carrier material, excipient, lubricant,buffer, antibacterial, bulking agent (such as mannitol), antioxidants(ascorbic acid or sodium bisulfite) or the like. Oral dosage forms arepreferred, although parenteral forms are quite satisfactory as well.

The dose administered must be carefully adjusted according to the age,weight, and condition of the patient, as well as the route ofadministration, dosage form and regimen, and the desired result. Ingeneral, the dosage forms described above may be administered containingamounts of SGLT-2 inhibitor of from about 1 to about 1000 mg per daypreferably from about 2 to about 400 mg per day, in single or divideddoses of one to four times daily.

Cytotoxic agents which may be employed in conjunction with the SGLT-2inhibitors, in accordance with the invention, may be administered in thesame or different dosage forms with the SGLT2 inhibitor.

Cytotoxic agents approved by the FDA such as those listed in thePhysicians' Desk Reference, 61^(st) Ed. (2007), which may be employedinclude doxorubicin, doxorubicin valerate, idarubicin HCl, mitomycin,paclitaxel, taxotere, teniposide, etoposide, carboplatin, busulfan,megestrol acetate, mitotane, altretamine, lomustine, carmustine,estramustine phosphate sodium, procarbazine hydrochloride, cytarabine,dasatinib, gemcitabine, as well as an apoptosis agonist, DNAtopoisomerase inhibitors, microtubule stimulants, beta tubulinantagonists, tubulin antagonist and microtubule inhibitors, thymidylatesynthase inhibitors, DNA antagonists, ErbB inhibitors, angiogenesisinhibitors, DNA topoisomerase ATP hydrolyzing inhibitors, DNAantagonists, endothelial growth factor receptor kinase inhibitors, p21stimulants, endothelial growth factor receptor kinase inhibitors, p21stimulants, microtubule inhibitors, dihydrofolate reductase inhibitors,such as ATP-binding cassette, subfamily B (MDR/TAP), member 1, Caspase3, colony stimulating factor 2, thymidylate synthetase, topoisomerase(DNA) I, tubuline beta polypeptide, Cyclin G1, Cyclin-dependent kinaseinhibitor 1A, kinase insert domain receptor (a type III receptortyrosine kinase), mucin 1 transmembrane, DNA(cytosine-5-)-methyltransferase 1, epidermal growth factor receptor, andeukaryotic translation elongation factor 1 alpha 1, as well as9-methoxyellipticine, and N-methylellipticinium,

prednimustine, WB4291 (1-[bis(2-chloroethyl)amino]-3-methylnaphthalene),daunomycin and vincristine.

Preferred cytotoxic agents to be employed herein will depend upon theparticularly neoplastic disease to be treated.

The various cytotoxic agents described above may be employed in dosagesand regimens as generally known in the art or in the PHYSICIANS' DESKREFERENCE (PDR) or REMINGTON'S PHARMACEUTICAL SCIENCES (Mack PublishingCo., Easton, Pa.).

Unless otherwise indicated, the dosages and formulations for the SGLT2inhibitor will be disclosed in the various patents and applicationsdiscussed above.

The various formulations of the invention may optionally include one ormore fillers or excipients in an amount within the range of from about 0to about 90% by weight and preferably from about 1 to about 80% byweight such as lactose, sugar, corn starch, modified corn starch,mannitol, sorbitol, inorganic salts such as calcium carbonate and/orcellulose derivatives such as wood cellulose and microcrystallinecellulose.

One or more binders may be present in addition to or in lieu of thefillers in an amount within the range of from about 0 to about 35% andpreferably from about 0.5 to about 30% by weight of the composition.Examples of such binders which are suitable for use herein includepolyvinylpyrrolidone (molecular weight ranging from about 5000 to about80,000 and preferably about 40,000), lactose, starches such as cornstarch, modified corn starch, sugars, gum acacia and the like as well asa wax binder in finely powdered form (less than 500 microns) such ascarnauba wax, paraffin, spermaceti, polyethylenes or microcrystallinewax.

Where the composition is to be in the form of a tablet, it will includeone or more tabletting lubricants in an amount within the range of fromabout 0.2 to about 8% and preferably from about 0.5 to about 2% byweight of the composition, such as magnesium stearate, stearic acid,palmitic acid, calcium stearate, talc, carnauba wax and the like. Otherconventional ingredients which may optionally be present includepreservatives, stabilizers, anti-adherents or silica flow conditionersor glidants, such as Syloid brand silicon dioxide as well as FD&Ccolors.

Tablets of the invention may also include a coating layer which maycomprise from 0 to about 15% by weight of the tablet composition. Thecoating layer may comprise any conventional coating formulations andwill include one or more film-formers or binders, such as a hydrophilicpolymer like hydroxypropylmethylcellulose, and/or a hydrophobic polymerlike methacrylic acid esters neutral polymer, ethyl cellulose, celluloseacetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinenepolymers, glyceryl esters of wood resins and the like and one or moreplasticizers, such as triethyl citrate, diethyl phthalate, propyleneglycol, glycerin, butyl phthalate, castor oil and the like. Both coretablets as well as coating formulations may contain aluminum lakes toprovide color.

The film formers are applied from a solvent system containing one ormore solvents including water, alcohols like methyl alcohol, ethylalcohol or isopropyl alcohol, ketones like acetone, or ethylmethylketone, chlorinated hydrocarbons like methylene chloride,dichloroethane, and 1,1,1-trichloroethane.

Where a color is employed, the color will be applied together with thefilm former, plasticizer and solvent compositions.

It will be recognized by one of skill in the art that the amount of drugrequired for therapeutic effect on administration will, of course, varywith the agent chosen, the nature and severity of the condition and themammal undergoing treatment, and is ultimately at the discretion of thephysician. Furthermore, the optimal quantity and spacing of individualdosages of a drug will be determined by the nature and extent of theweight loss desired, the form, route and site of administration, theparticular patient being treated and that such optima can be determinedby conventional techniques. It will also be appreciated that the optimalcourse of treatment, this is, the number of doses given, can beascertained by those skilled in the art using conventional course oftreatment determination tests.

An example of a preferred formulation containing an SGLT2 inhibitor foruse herein and a process for preparing such formulation are set out inU.S. Provisional Application Ser. No. 60/896,286 filed Mar. 22, 2007,the disclosure of which is incorporated herein by reference in itsentirety for any purpose.

Preferred tablet formulations in accordance with the invention are setout below.

Preferred Range Material Range %/mg by weight %/mg by weight of 200 mgTablet of 200 mg tablet tablet Dapagliflozin 0.1 to 70%/0.2 to 140 mg 1to 50%/2 to 100 mg Bulking Agent 2 to 95%/4 to 190 mg 10 to 85%/20 to170 mg Lactose 0 to 95%/0 to 190 mg 20 to 75%/10 to 100 mgMicrocrystalline cellulose 0 to 95%/0 to 190 mg 20 to 75%/40 to 150 mgDisintegrant 0 to 20%/0 to 40 mg 0.25 to 10%/0.5 to 20 mg Croscarmellosesodium 0 to 20%/0 to 40 mg 2 to 10%/4 to 20 mg Crospovidone 4 to 12%/4to 20 mg 6 to 10%/12 to 20 mg Lubricant 0.1 to 5%/0.2 to 10 mg 0.2 to2%/0.4 to 4 mg Magnesium Stearate 0.1 to 5%/0.2 to 10 mg 0.2 to 2%/0.4to 4 mg Anti adherent/glidant 0 to 20%/0 to 40 mg 1 to 4%/2 to 8 mgTalc, silicon dioxide %/mg by weight of %/mg by weight of 200 mg OuterProtective Coating Layer 200 mg tablet tablet Coating polymer, andoptional 0.5 to 50%/1 to 100 mg 1 to 5%/2 to 10 mg plasticizer, glidantsand color

Preferred stock granulation formulations (for use in capsules) inaccordance with the invention are set out below.

Range Preferred Range Material %/mg by weight of %/mg by weight ofTablet 200 mg tablet 0.1 200 mg tablet Dapagliflozin to 70%/0.2 to 140mg 1 to 50%/2 to 100 mg Bulking Agent/Binder 2 to 95%/4 to 190 mg 10 to85%/20 to 170 mg Microcrystalline 1 to 95%/1 to 190 mg 20 to 75%/10 to100 mg cellulose Pregelatinized starch 0 to 95%/0 to 190 mg 20 to 75%/40to 150 mg Disintegrant 0 to 20%/0 to 40 mg 0.25 to 10%/0.5 to 20 mgSodium Starch 0 to 20%/0 to 40 mg 2 to 10%/4 to 20 mg glycolateLubricant 0.1 to 5%/0.2 to 10 mg 0.2 to 2%/0.4 to 4 mg MagnesiumStearate 0.1 to 5%/0.2 to 10 mg 0.2 to 2%/0.4 to 4 mg Antiadherent/glidant 0 to 20%/0 to 40 mg 1 to 4%/2 to 8 mg Talc silicondioxide

The pharmaceutical formulation for use in the method of the invention inthe form of a tablet or capsule may be obtained by a process whichincludes the steps of:

a) formulating granules by wet granulation of the SGLT2 inhibitor,

b) blending the granules with a tableting aid and diluent,

c) tabletting the blend thus obtained into tablets, or

d) loading the granules into capsules.

The mixture used for forming the granules includes a granulating binder.The granulating binder is preferably a polyvinylpyrrolidone such as, forexample, a polyvinylpyrrolidone having a molecular weight of 45,000. Thepolyvinylpyrrolidone may be used in a proportion of 2 to 4% by weightwith respect to the final tablet.

After the granulating step, the granules may be sieved and dried.

The granules are then blended with a diluent and tableting aid. Thediluent may be a conventional filler usually used for making tablets,such as microcrystalline cellulose. The tableting aid may be aconventional material, such as magnesium stearate.

A typical injectable preparation is produced by aseptically placing 50mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

SGLT2 inhibitor activity of the compounds of the invention may bedetermined by use of an assay system as set out below.

Assay for SGLT2 Activity

The mRNA sequence for human SGLT2 (GenBank No. M95549) was cloned byreverse-transcription and amplification from human kidney mRNA, usingstandard molecular biology techniques. The cDNA sequence was stablytransfected into CHO cells, and clones were assayed for SGLT2 activityessentially as described in Ryan et al. (1994) (cited below). Evaluationof inhibition of SGLT2 activity in a clonally selected cell line wasperformed essentially as described in Ryan et al., with the followingmodifications. Cells were grown in 96-well plates for 2-4 days to 75,000or 30,000 cells per well in F-12 nutrient mixture (Ham's F-12), 10%fetal bovine serum, 300 ug/ml Geneticin and penicillin-streptomycin. Atconfluence, cells were washed twice with 10 mM Hepes/Tris, pH 7.4, 137mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgSO₄. Cellsthen were incubated with 10 μM [¹⁴C]AMG, and 10 μM inhibitor (finalDMSO=0.5%) in 10 mM Hepes/Tris, pH 7.4, 137 mM NaCl, 5.4 mM KCl, 2.8 mMCaCl₂, 1.2 mM MgSO₄ at 37° C. for 1.5 hr. Uptake assays were quenchedwith ice cold 1×PBS containing 0.5 mM phlorizin, and cells were thenlysed with 0.1% NaOH. After addition of MicroScint scintillation fluid,the cells were allowed to shake for 1 hour, and then [¹⁴C]AMG wasquantitated on a TopCount scintillation counter. Controls were performedwith and without NaCl. For determination of EC₅₀ values, 10 inhibitorconcentrations were used over 2 log intervals in the appropriateresponse range, and triplicate plates were averaged across plates. Ryan,M. J., Johnson, G., Kirk, J., Fuerstenberg, S. M., Zager, R. A. andTorok-Storb, B., “HK-2: an immortalized proximal tubule epithelial cellline from normal adult human kidney”, Kidney International, 45:48-57(1994).

EXAMPLES

The following working Examples are illustrative of the invention. Alltemperatures are expressed in degrees Centigrade unless otherwiseindicated.

Examples 1 to 3

Capsules containing compound I were prepared in strengths of 2.5 mg(Example 1), 10 mg (Example 2) and 100 mg (Example 3) as two-piece, grayopaque size #0 (2.5 mg and 10 mg) and size #00 (for 0 mg) hard gelatincapsules.

Examples 1 and 2

Composition: 25.0 mg of Granulation containing compound I for Capsules(10.0% w/was the non-solvated form), filled in Gray, Opaque, Size #0Capsule Shell.

A. Stock Granulation Composition

Ingredient Amount (% w/w) Compound I¹ 10.0 Pregelatinized Starch, NF15.0 Microcrystalline Cellulose, NF² 68.75 Sodium Starch Glycolate, NF3.0 Silicon Dioxide, NF 2.0 Magnesium Stearate, NF³ 1.25 ¹This amount isexpressed in terms of the amount of compound I at 100% purity. The exactamount will vary depending on the purity of compound I. ²The amount ofmicrocrystalline cellulose used will vary depending on the purity ofcompound I. ³The preferred amount is 1.25% (w/w). The range is1.25-1.50% (w/w).

The stock granulation of Part A and the Example 1 and Example 2 capsuleswere prepared according to the following procedures.

Example 1 B. Example 1 Stock Granulation Procedure

1. Screen compound I.

2. Screen silicon dioxide.

3. Mix silicon dioxide with compound I in a suitable blender.

4. Screen pregelatinized starch and microcrystalline cellulose, ifnecessary.

5. Add ingredients from Step 4 to a suitable blender.

6. Add mixture from Step 3 to the blend from Step 5, and mix.

7. Screen sodium starch glycolate.

8. Add ingredient from Step 7 to the blend from Step 6, and mix.

9. Screen the blend from Step 8, and mix.

10. Screen portion of magnesium stearate.

11. Add ingredient from Step 10 to the blend from Step 9, and mix.

12. Densify the blend from Step 11.

13. Reduce the densified blend Step 12.

14. Screen the remaining portion of magnesium stearate.

15. Add ingredient from Step 14 to the granulation from Step 13, andmix.

C. Example 1 Product Compound I Capsule, 2.5 mg (As the Non-SolvatedForm)

1. Fill empty capsule shells with sufficient Example 1 Part A stockgranulation for capsules (10.0%) w/w (as the non-solvated form), toprovide 2.5 mg capsules.

2. De-dust the capsules.

Example 2 Product Compound I Capsule, 10 mg (As the Non-Solvated Form)

1. Fill empty capsule shells with Example 1 Part A stock granulation forcapsules (10.0% w/w as the non-solvated form), to provide 10 mgcapsules.

2. De-dust the capsules.

3. Weight sort the capsules.

The Example 1 (2.5 mg) and Example 2 (10 mg) capsules are used intreating obesity.

Example 3 Compound I Capsule, 100 mg

Composition: 438.6 mg of compound I (Example 3 Part A) Stock Granulationfor Capsules (22.8% w/w as the non-solvated form), filled in Gray,Opaque, Size #0 Capsule Shell.

A. Stock Granulation Composition

Ingredient Amount (% w/w) Compound I¹ 22.8 Pregelatinized Starch, NF15.0 Microcrystalline Cellulose, NF² 55.95 Sodium Starch Glycolate, NF3.0 Silicon Dioxide, NF 2.0 Magnesium Stearate, NF³ 1.25 ¹This amount isexpressed in terms of the amount of compound I at 100% purity. The exactamount will vary depending on the purity of compound I. ²The amount ofmicrocrystalline cellulose used will vary depending on the purity ofcompound I. ³The preferred amount is 1.25% (w/w). The range is1.25-1.50% (w/w).

The stock granulation of Part A and the Example 3 capsules were preparedaccording to the following procedures.

B. Stock Granulation Procedure

1. Screen silicon dioxide.

2. Mix silicon dioxide with compound I in a suitable blender.

3. Screen the blend from Step 2, and mix again.

4. Screen pregelatinized starch and microcrystalline cellulose, ifnecessary.

5. Add ingredients form Step 4 to the blend from Step 3, and mix.

6. Screen sodium starch glycolate.

7. Add ingredient from Step 6 to the blend from Step 5, and mix.

8. Screen a portion of magnesium stearate.

9. Add ingredient from Step 8 to the blend from Step 7, and mix.

10. Densify the blend from Step 9.

11. Reduce the densified blend from Step 10.

12. Screen the remaining portion of magnesium stearate.

13. Add ingredient from Step 12 to the granulation from Step 11, andmix.

C. Example 3 Product: Compound I Capsule, 100 mg (As the Non-SolvatedForm)

1. Fill empty capsule shells with Example 3 stock granulation forcapsules (22.8% w/w as the non-solvated form).

2. De-dust the capsules.

3. Weight sort the capsules.

The so-formed capsules of Example 1 (2.5 mg), Example 2 (10 mg) andExample 3 (100 mg) are used to inhibit or prevent rejection of renaltransplant rejection.

Examples 4 to 6

Tablets containing the SGLT2 inhibitor compound Ia (the (S) propyleneglycol solvate or (S) propylene glycol hydrate of compound I) wereprepared in strengths of 2.5 mg (Example 4), 10 mg (Example 5) and 50 mg(Example 6) as described below.

Example 4 Product Compound Ia Tablet, 2.5 mg A. Tablet Composition

Ingredient Amount Compound Ia¹ 3.075 mg Microcrystalline Cellulose, NF²67.113 mg  Lactose Anhydrous, NF 25.000 mg  Crospovidone, NF 8.750 mgCroscarmellose Sodium, NF 3.750 mg Talc, USP 12.500 mg  Silicon Dioxide,NF 2.875 mg Magnesium Stearate, NF³ 1.938 mg ¹Compound Ia is a propyleneglycol solvate. The amount of non-solvated compound I is theoreticallyequivalent to 81.29% of compound Ia. The actual amount of compound Iawill depend on the “As Is” purity of the drug. ²This is the compensatingexcipient. The amount used may vary depending on the “As Is” purity ofthe drug and/or the actual amount of magnesium stearate used. ³Thetarget amount is 1.94 mg. Acceptable range is 1.55-2.33 mg.

The stock granulation of Part A and the Example 4 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

1. Deaggregate compound Ia and magnesium stearate separately using asuitable screen.

2. Mix compound Ia with a portion of microcrystalline cellulose in asuitable mixer and transfer it into a suitable blender.

3. “Dry Rinse” the mixer used for mixing Step 2 with a portion ofmicrocrystalline cellulose.

4. Add the blend from Step 3 to the blend from Step 2.

5. Mix the mixture from Step 4 with remaining microcrystallinecellulose, portion of crospovidone, portion of croscarmellose sodium,portion of silicon dioxide and lactose anhydrous.

6. Add talc and intragranular magnesium stearate to the mixture fromStep 5 and mix.

7. Compact the powder blend from Step 6.

8. Reduce compact from Step 7 to form granules.

9. Mix the granules from Step 8 with remaining amounts of crospovidone,croscarmellose sodium and silicon dioxide.

10. Mix the granules from Step 9 with remaining amount of magnesiumstearate.

C. Example 4 Product: Compound Ia Tablet, 2.5 mg

1. Setup the tabletting equipment.

2. Compress the Example 4 stock granulation into tablets (2.46% w/w),(2.5 mg).

Example 5 Product Compound Ia Tablet, 10 mg A. Tablet Composition

Ingredient Amount Compound Ia¹ 12.300 mg Microcrystalline Cellulose, NF²57.888 mg Lactose Anhydrous, NF 25.000 mg Crospovidone, NF  8.750 mgCroscarmellose Sodium, NF  3.750 mg Talc, USP 12.500 mg Silicon Dioxide,NF  2.875 mg Magnesium Stearate, NF³  1.938 mg ¹Compound Ia is apropylene glycol solvate. The amount of non-solvated compound Ia istheoretically equivalent to 81.29% of compound Ia. The actual amount ofcompound Ia will depend on the “As Is” purity of the drug. ²This is thecompensating excipient. The amount used may vary depending on the “AsIs” purity of the drug and/or the actual amount of magnesium stearateused. ³The target amount is 1.94 mg. Acceptable range is 1.55-2.33 mg.

The stock granulation of Part A and the Example 5 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

1. Deaggregate compound Ia and magnesium stearate separately using asuitable screen.

2. Mix microcrystalline cellulose, compound Ia portion of crospovidone,portion of croscarmellose sodium, portion of silicon dioxide and lactoseanhydrous in a suitable blender.

3. Add talc and intragranular magnesium stearate to the mixture fromStep 2 and mix in a suitable blender.

4. Compact the powder blend from Step 3.

5. Reduce compact from Step 4 to form granules.

6. Mix the granules from Step 5 with remaining amounts of crospovidone,croscarmellose sodium and silicon dioxide.

7. Mix the granules from Step 6 with remaining amount of magnesiumstearate.

C. Example 5 Product: Compound Ia Tablet, 10 mg

1. Setup the tabletting equipment.

2. Compress the Example 5 stock granulation into tablets (9.84% w/w).

Example 6 Product Compound Ia Tablet, 50 mg A. Tablet Composition

Ingredient Amount Compound Ia¹ 61.660 mg Microcrystalline Cellulose, NF²114.090 mg  Lactose Anhydrous, NF 62.600 mg Crospovidone, NF 21.910 mgCroscarmellose Sodium, NF  9.390 mg Talc, USP 31.300 mg Silicon Dioxide,NF  7.200 mg Magnesium Stearate, NF³  4.850 mg ¹The amount shown isbased on the amount of compound Ia at 100% purity. The exact amount mayvary depending on the “As Is” purity of compound Ia. ²This is thecompensating excipient. The amount used may vary depending on the “AsIs” purity of the drug and/or the actual amount of magnesium stearateused. ³The target amount is 4.85 mg. Acceptable range is 3.76-5.95 mg.

The stock granulation of Part A and the Example 6 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

1. Mix compound Ia microcrystalline cellulose, lactose anhydrous,crospovidone, croscarmellose sodium, talc and silicon dioxide in asuitable blender.

2. Pass the mixture from Step 1 through a suitable mill.

3. Determine the yield from Step 1 and calculate the amount of magnesiumstearate required.

4. Mix the mixture from Step 2 in a suitable blender.

5. Mix the mixture from Step 4 with magnesium stearate.

6. Dry granulate the powder blend from Step 5.

7. Size the granulation from Step 6.

8. Determine the yield based on Step 7.

9. Mix the granules from Step 8 with remaining amount of crospovidone,croscarmellose sodium and silicon dioxide.

10. Mix the granules from Step 9 with remaining amount of magnesiumstearate.

C. Example 6 Product: Compound Ia PGS Tablet, 50 mg

1. Setup the tabletting equipment.

2. Compress the Example 6 stock granulation (19.7% w/w), into tablets(50 mg).

The so-formed tablets of Example 4 (2.5 mg), Example 5 (10 mg) andExample 6 (50 mg) are used to inhibit or prevent rejection of renaltransplant rejection.

Example 7

An oral solution (0.5 mg/mL) was prepared by dissolving compound I in amixture of polyethylene glycol 400, NF and water for injection, USP orpurified water (30:70% v/v). The oral solution was clear and colorless.It is used to inhibit or prevent renal transplant rejection.

Example 8

The glucosuric effects of compound Ia results in significant loss ofcalories in the urine versus a known SGLT2 inhibitor (GSK 869,682).Thus, as seen in FIG. 1, the results of an indirect comparison of twosingle ascending dose studies of SGLT2 inhibitors is shown. The panel atthe top of FIG. 1 is from a presentation by GSK in an analyst meeting,showing the amount of glucose excretion/day in healthy subjects taking50, 100, 200 or 500 mg of GSK 869,682. The panel at the bottom is fromstudy MB-102001, showing the amount of glucose excretion/day in healthysubjects taking 5, 20, 50 or 100 mg of compound Ia. This is furtherconfirmed in a 14-day multiple ascending dose phase 2a study in subjectswith type 2 diabetes. Results from the 24-hour glucose excretion areshown in FIG. 2 for all subjects in the MB-102003 study. The mean urineglucose is in the darker lines. Compared to subjects on placebo, who hadlow urine glucose excretion, subjects randomized to compound Ia hadhigher urine glucose excretion.

1. A method for treating cancers that express SGLT2 levels higher thannormal cells in a mammal comprising administering to the mammal in needof such treatment a therapeutically effective amount of an SGTL2inhibitor.
 2. The method according to claim 1 wherein the mammal is ahuman.
 3. The method according to claim 2 wherein the cancer is lungcancer metastatic lesions.
 4. The method according to claim 2 whereinthe cancer is lung cancer metastatic lesions of the liver.
 5. The methodaccording to claim 2 wherein the cancer is lung cancer metastaticlesions of the lymph nodes.
 6. The method according to claim 1 whereinthe SGLT2 inhibitor is a C-glucoside or an O-glucoside.
 7. The methodaccording to claim 1 wherein the amount of SGLT2 inhibitor has

the structure wherein R¹, R² and R^(2a) are independently hydrogen, OH,OR⁵, alkyl, CF₃, OCHF₂, OCF₃, SR^(5i) or halogen, or two of R¹, R² andR^(2a) together with the carbons to which they are attached can form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R³ and R⁴ are independently hydrogen, OH, OR^(5a), OAryl, OCH₂Aryl,alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5b), —CO₂H,COR^(6b), —CH(OH)R^(6c), —CH(OR^(5h))R^(6d), —CONR⁶R^(6a), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl, or a five, six or seven membered heterocycle which may contain1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³and R⁴ together with the carbons to which they are attached form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h)and R^(5i) are independently alkyl; R⁶, R^(6a), R^(6b), R^(6c), andR^(6d) are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl,or R⁶ and R^(6a) together with the nitrogen to which they are attachedform an annelated five, six or seven membered heterocycle which maycontain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; A is O, S, NH, or (CH₂)_(n) where n is 0-3, or a pharmaceuticallyacceptable salt, stereoisomer, or prodrug ester thereof with the provisothat where A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is 0, and atleast one of R¹, R², and R^(2a) is OH or OR⁵, then at least one of R¹,R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴is CF₃, —OCHF₂, —OCF₃, —CN, —CO₂R^(5b), CH(OR^(5h))R^(6d), CH(OH)R^(6c),COR^(6b), —NHCOR^(5c), —NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e),—SOR^(5f), —SO₂R^(5g) or —SO₂Aryl.
 8. The method according to claim 1wherein the SGLT2 inhibitor has the structure

or a pharmaceutically acceptable salt, a stereoisomer thereof, or aprodrug ester thereof
 9. The method according to claim 1 wherein theSGLT2 inhibitor has the structure


10. The method as defined in claim 1 wherein the SGLT2 inhibitor has thestructure

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof,or a prodrug ester thereof.
 11. A method for treating cancers thatexpress SGLT2 levels higher than normal cells in a mammal comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor and at least one pharmaceutically acceptable carrier,excipient, or diluent.
 12. The method according to claim 11 wherein themammal is a human.
 13. The method according to claim 12 wherein thecancer is lung cancer metastatic lesions.
 14. The method according toclaim 12 wherein the cancer is lung cancer metastatic lesions of theliver.
 15. The method according to claim 12 wherein the cancer is lungcancer metastatic lesions of the lymph nodes.
 16. The method accordingto claim 11 wherein the SGLT2 inhibitor is a C-glucoside or anO-glucoside.
 17. The method according to claim 11 wherein the amount ofSGLT2 inhibitor has the structure

wherein R¹, R² and R^(2a) are independently hydrogen, OH, OR⁵, alkyl,CF₃, OCHF₂, OCF₃, SR^(5i) or halogen, or two of R¹, R² and R^(2a)together with the carbons to which they are attached can form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R³ and R⁴ are independently hydrogen, OH, OR^(5a), OAryl, OCH₂Aryl,alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5b), —CO₂H,COR^(6b), —CH(OH)R^(6c), —CH(OR^(5h))R^(6d), —CONR⁶R^(6a), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl, or a five, six or seven membered heterocycle which may contain1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³and R⁴ together with the carbons to which they are attached form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h)and R^(5i) are independently alkyl; R⁶, R^(6a), R^(6b), R^(6c), andR^(6d) are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl,or R⁶ and R^(6a) together with the nitrogen to which they are attachedform an annelated five, six or seven membered heterocycle which maycontain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; A is O, S, NH, or (CH₂)_(n) where n is 0-3, or a pharmaceuticallyacceptable salt, stereoisomer, or prodrug ester thereof with the provisothat where A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is O, and atleast one of R¹, R², and R^(2a) is OH or OR⁵, then at least one of R′,R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴is CF₃, —OCHF₂, —OCF₃, —CN, —CO₂R^(5b), CH(OR^(5h))R^(6d), CH(OH)R^(6c),COR^(6b), —NHCOR^(5c), —NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e),—SOR^(5f), —SO₂R^(5g) or —SO₂Aryl.
 18. The method according to claim 11wherein the SGLT2 inhibitor has the structure

or a pharmaceutically acceptable salt, a stereoisomer thereof, or aprodrug ester thereof.
 19. The method according to claim 11 wherein theSGLT2 inhibitor has the structure


20. The method as defined in claim 11 wherein the SGLT2 inhibitor hasthe structure

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof,or a prodrug ester thereof.
 21. A method for treating cancers thatexpress SGLT2 levels higher than normal cells in a mammal comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of an SGLT2 inhibitor and a cytotoxic agent where thecytotoxic agent is administered prior to, after, or concurrently withthe SGLT2 inhibitor.
 22. The method according to claim 21 wherein themammal is a human.
 23. The method according to claim 22 wherein thecancer is lung cancer metastatic lesions.
 24. The method according toclaim 22 wherein the cancer is lung cancer metastatic lesions of theliver.
 25. The method according to claim 22 wherein the cancer is lungcancer metastatic lesions of the lymph nodes.
 26. The method accordingto claim 21 wherein the SGLT2 inhibitor is a C-glucoside or anO-glucoside.
 27. The method according to claim 21 wherein the amount ofSGLT2 inhibitor has the structure

wherein R¹, R² and R^(2a) are independently hydrogen, OH, OR⁵, alkyl,CF₃, OCHF₂, OCF₃, SR^(5i) or halogen, or two of R′, R² and R^(2a)together with the carbons to which they are attached can form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R³ and R⁴ are independently hydrogen, OH, OR^(5a), OAryl, OCH₂Aryl,alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5b), —CO₂H,COR^(6b), —CH(OH)R^(6c), —CH(OR^(5h))R^(6d), —CONR⁶R^(6a), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl, or a five, six or seven membered heterocycle which may contain1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³and R⁴ together with the carbons to which they are attached form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R⁵, R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h)and R^(5i) are independently alkyl; R⁶, R^(6a), R^(6b), R^(6c), andR^(6d) are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl,or R⁶ and R^(6a) together with the nitrogen to which they are attachedform an annelated five, six or seven membered heterocycle which maycontain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; A is O, S, NH, or (CH₂)_(n) where n is 0-3, or a pharmaceuticallyacceptable salt, stereoisomer, or prodrug ester thereof; with theproviso that where A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is O,and at least one of R¹, R², and R^(2a) is OH or OR⁵, then at least oneof R¹, R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³and R⁴ is CF₃, —OCHF₂, —OCF₃, —CN, —CO₂R^(5b), CH(OR^(5h))R^(6d),CH(OH)R^(6c), COR^(6b), —NHCOR^(5c), —NHSO₂R^(5d), —NHSO₂Aryl, Aryl,—SR^(5e), —SOR^(5f), —SO₂R^(5g) or —SO₂Aryl.
 28. The method according toclaim 21 wherein the SGLT2 inhibitor has the structure

or a pharmaceutically acceptable salt, a stereoisomer thereof, or aprodrug ester thereof.
 29. The method according to claim 21 wherein theSGLT2 inhibitor has the structure


30. The method as defined in claim 21 wherein the SGLT2 inhibitor hasthe structure

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof,or a prodrug ester thereof
 31. A method for treating cancers thatexpress SGLT2 levels higher than normal cells in a mammal comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising an SGLT2inhibitor, a cytotoxic agent and at least one pharmaceuticallyacceptable carrier, excipient, or diluent.
 32. The method according toclaim 31 wherein the mammal is a human.
 33. The method according toclaim 32 wherein the cancer is lung cancer metastatic lesions.
 34. Themethod according to claim 32 wherein the cancer is lung cancermetastatic lesions of the liver.
 35. The method according to claim 32wherein the cancer is lung cancer metastatic lesions of the lymph nodes.36. The method according to claim 31 wherein the SGLT2 inhibitor is aC-glucoside or an O-glucoside.
 37. The method according to claim 31wherein the amount of SGLT2 inhibitor has the structure

wherein R¹, R² and R^(2a) are independently hydrogen, OH, OR⁵, alkyl,CF₃, OCHF₂, OCF₃, SR^(5i) or halogen, or two of R¹, R² and R^(2a)together with the carbons to which they are attached can form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R³ and R⁴ are independently hydrogen, OH, OR^(5a), OAryl, OCH₂Aryl,alkyl, cycloalkyl, CF₃, —OCHF₂, —OCF₃, halogen, —CN, —CO₂R^(5b), —CO₂H,COR^(6b), —CH(OH)R^(6c), —CH(OR^(5h))R^(6d), —CONR⁶R^(6a), —NHCOR^(5c),—NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e), —SOR^(5f), —SO₂R^(5g),—SO₂Aryl, or a five, six or seven membered heterocycle which may contain1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO₂, or R³and R⁴ together with the carbons to which they are attached form anannelated five, six or seven membered carbocycle or heterocycle whichmay contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; R⁵, R^(5a), R^(5b), R^(6c), R^(5d), R^(6e), R^(5f), R^(5g), R^(5h)and R^(5i) are independently alkyl; R⁶, R^(6a), R^(6b), R^(6c), andR^(6d) are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl,or R⁶ and R^(6a) together with the nitrogen to which they are attachedform an annelated five, six or seven membered heterocycle which maycontain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/orSO₂; A is O, S, NH, or (CH₂)_(n) where n is 0-3, or a pharmaceuticallyacceptable salt, stereoisomer, or prodrug ester thereof with the provisothat where A is (CH₂)_(n) where n is 0, 1, 2, or 3 or A is O, and atleast one of R¹, R², and R^(2a) is OH or OR⁵, then at least one of R¹,R², and R^(2a) is CF₃, OCF₃, or OCHF₂ and/or at least one of R³ and R⁴is CF₃, —OCHF₂, —OCF₃, —CN, —CO₂R^(5b), CH(OR^(5h))R^(6d), CH(OH)R^(6c),COR^(6b), —NHCOR^(5c), —NHSO₂R^(5d), —NHSO₂Aryl, Aryl, —SR^(5e),—SOR^(5f), —SO₂R^(5g) or —SO₂Aryl.
 38. The method according to claim 31wherein the SGLT2 inhibitor has the structure

or a pharmaceutically acceptable salt, a stereoisomer thereof, or aprodrug ester thereof
 39. The method according to claim 31 wherein theSGLT2 inhibitor has the structure


40. The method as defined in claim 31 wherein the SGLT2 inhibitor hasthe structure

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof,or a prodrug ester thereof.